Is reversal of endothelial dysfunction still an attractive target in modern cardiology?

Table 1 Large studies evaluating the prognostic value of flow-mediated dilation

Ref.	Number of patients	Cohort	Asymptomatic Patients?	Length of follow-up (mo)	Outcome	Result	Independent value of FMD?
Rossi et al[45]	2264	Post-menopausal women	Yes	45 ± 13	CV death, MI, revascularisation, TIA, stroke	FMD was a predictor of MACE independently of traditional cardiac risk factors.	Yes
Patti et al[56]	136	Patients with single-vessel coronary artery disease undergoing PCI	No	6	In-stent restenosis	Patients with impaired FMD were more likely to suffer in-stent restenosis.	Yes
Gokce et al[59]	187	Patients undergoing vascular surgery	No	1	CV death, MI, unstable angina, ventricular fibrillation, stroke, raised troponin	FMD was an independent predictor of MACE in the immediate post-operative period.	Yes
Brevetti et al[58]	139	Patients with peripheral arterial disease	No	23 ± 10	CV death, MI, revascularisation, TIA, critical limb ischaemia	FMD was an independent predictor of events over the follow-up period.	Yes
Chan et al[53]	152	Patients with coronary artery disease	No	34 ± 10	CV death, MI, revascularisation, claudication	FMD was a strong independent predictor of risk even accounting for carotid plaque burden.	Yes
Shimbo et al[47]	842	Asymptomatic multi-ethnic cohort	Yes	36	Vascular death, MI, stroke	FMD was able to predict adverse events but not independently.	No
Suzuki et al[43]	819	Asymptomatic multi-ethnic cohort including patients with metabolic syndrome	Yes	81 ± 21	Vascular death, MI, stroke	Patients with the combination of metabolic syndrome and endothelial dysfunction had a significantly worse outcome.	No
Yeboah et al[44]	2792	Mixed cohort of patients > 65 yr	No	60	CVD death, MI, stroke, congestive heart failure, claudication, revascularisation	FMD was an independent predictor of risk but added little to traditional risk stratification.	Yes
Muiesan et al[57]	172	Hypertensive patients	No	95 ± 37	CV death, MI, revascularisation, arrhythmia, TIA, critical limb ischaemia, retinal artery occlusion	FMD below median was independently associated with adverse outcome.	Yes
Shechter et al[46]	618	Healthy subjects (mixed)	Yes	55.2 ± 21.6	CV death, MI, stroke, congestive revascularisation	FMD predicted adverse outcome independently.	Yes
Katz et al[77]	259	Heart failure patients (LVEF < 40% and NYHA class 2-3)	No	28	Death or cardiac transplantation	FMD is associated with increased adverse outcome in ischaemic and non-ischaemic heart failure.	Yes

PCI: Percutaneous coronary intervention; MACE: Adverse major cardiovascular events; MI: Myocardial infarction; TIA: Transient ischaemic attack; FMD: Flow-mediated dilation.

Table 2 Selected studies examining pharmacological reversal of endothelial dysfunction

Ref.	Drug	Cohort	Design	Results
Mancini et al[94]	Quinapril	105 normotensive patients with coronary artery disease	Randomised double-blind, placebo controlled	Quinapril improved endothelial function compared to placebo as measured by coronary artery diameter response to acetylcholine
Higashi et al[96]	Various ACE inhibitors, beta-blockers, calcium channel blockers and diuretics	296 hypertensive patients	Multi-centre cohort study	ACE inhibitors significantly improved endothelial dependent vasodilatation compared to other drug classes as measured by forearm blood flow
Wassmann et al[97]	Candesartan, felodipine	47 patients with high cholesterol	Randomised double-blind, placebo controlled	Candesartan improved forearm blood flow compared to felodipine or placebo
Ghiadoni et al[98]	Nifedipine, amlodipine Perindopril, telmisartan, atenolol, nebivolol	168 patients with hypertension	Randomized, single-blind, parallel-group	Only perindopril improved FMD (although perindopril, telmisartan, nifedipine and amlodipine reduced oxidative stress and increased plasma antioxidant capacity)
Tzemos et al[99]	Valsartan, amlodipine	25 hypertensive patients	Randomised double-blind, crossover	Valsartan improved forearm blood flow
Takagi et al[100]	Telmisartan	Mixed; 398 patients	Meta-analysis of 7 studies	Statistically significant increase in FMD by 48.7%
Farquaharson et al[101]	Spironolactone	10 patients with NYHA class I-II heart failure	Randomised, double-blind placebo-controlled crossover study	Spironolactone improved forearm blood flow compared to placebo
MacDonald et al[103]	Spironolactone	43 patients with NYHA class I-II heart failure	Randomised, double-blind crossover study	Spironolactone improved forearm blood flow compared to placebo
Abiose et al[104]	Spironolactone	20 patients with NYHA class III-IV congestive heart failure	Cohort study	Spironolactone improved FMD at 4 wk with a sustained improvement at 8 wk
Tzemos et al[107]	Nebivolol, atenolol	12 hypertensive patients	Randomised, double-blind crossover study	Only nebivolol was able to improve endothelial dependent vasodilation
Pasini et al[108]	Nebivolol, atenolol	40 hypertensive patients with 40 controls	Randomised double-blind parallel group	FMD improved only in the group treated with nebivolol
Matsuda et al[109]	Carvedilol	29 patients with coronary artery disease	Randomised, placebo controlled	Carvedilol significantly improved FMD after 4 mo treatment
Agewall et al[116]	Atorvastatin	20 healthy smokers, 20 healthy non-smokers	Open label placebo controlled randomised cross-over	Smokers had a lower baseline FMD. Atorvastatin improved FMD in smokers but had no effect in non-smokers
Ostad et al[117]	Atorvastatin, ezetimibe	58 patients with coronary artery disease	Double-blind, randomised, parallel group	High-dose atorvastatin improved FMD significantly more than low dose atorvastatin + ezetimibe independently of improvement in LDL cholesterol
Gounari et al[118]	Rosuvastatin, ezetimibe	Patients with heart failure	Double-blind, placebo controlled, cross-over trial	Rosuvastatin caused a significant improvement of FMD compared to ezetimibe and independent of LDL cholesterol and baseline brachial artery diameter
Pitocco et al[121]	Metformin	42 type 1 diabetics without overt cardiovascular disease	Randomised double-blind, placebo controlled	Significant improvement in FMD by 1.32% compared to placebo
Lamendola et al[122]	Ranolazine	30 type 2 (non-insulin dependent) diabetics without overt cardiovascular disease	Randomised double-blind, placebo controlled	Significant improvement in FMD compared to placebo after 2 wk of ranolazine therapy
Kao et al[123]	Allopurinol	67 patients with CKD stage 3 and LV hypertrophy	Randomized, double-blind, parallel-group	Significant improvement in FMD compared to placebo after 9 mo of allopurinol therapy

FMD: Flow-mediated dilation.